ROLE OF THE STRIATAL-SPECIFIC RGS PROTEIN RGS9-2, IN CELLULAR SIGNALING PATHWAYS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们提供的数据表明RGS 9 -2在纹状体运动控制以及精神分裂症和帕金森病药物治疗的运动副作用中发挥作用。 例如，我们发现RGS 9基因敲除小鼠出现异常运动，与药物诱导的运动障碍（DID）非常相似。 DID是帕金森病和精神分裂症药物治疗的不明原因的运动副作用，被认为是由相应药物对纹状体D2-多巴胺受体（D2 R）的慢性作用引起的。 此外，我们发现RGS 9 -2靶向D2 R，并提出RGS 9 -2在纹状体神经元中功能上或空间上区分D2 R。 因此，药物诱导的RGS 9 -2介导的纹状体D2 R细胞区室化的改变可能导致异常的纹状体信号处理和药物诱导的异常不自主运动。 确定这种区室化是如何改变的将需要更好地理解我们以前的研究所提出的D2 R-RGS 9 -2相互作用。 因此，我们将继续我们的研究，将测试靶向RGS 9 -2到D2 R是否涉及直接或间接的相互作用，并绘制相互作用表面。 我们还将尝试重建D2 R和离子通道之间的耦合，例如产生和塑造纹状体信号的NMDA受体。 我们将测试共表达的RGS 9 -2是否可以改变D2 R通道偶联。 从一个平行的临床研究，我们已经确定了非同义突变和内含子缺失的RGS 9基因，是丰富的精神分裂症和帕金森氏病患者。 因此，我们将测试这些RGS 9基因变异导致RGS 9 -2细胞功能改变的假设。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have provided data suggesting a role for RGS9-2 in the striatal control of movement and in the movements side-effects of the pharmacotherapy of schizophrenia and Parkinson's disease. For example we showed that RGS9 knockout mice develop abnormal movements that closely resemble drug-induced dyskinesias (DID). DID are unexplained movement side-effects of the pharmacotherapy of Parkinson's disease and schizophrenia, and are thought to result from the chronic actions of the respective drugs on striatal D2-dopamine receptors (D2R). In addition we showed that RGS9-2 targets to D2R and proposed that RGS9-2 either functionally or spatially compartmentalizes D2R in striatal neurons. Thus drug-induced alterations in RGS9-2 mediated striatal D2R cellular compartmentalization may lead to abnormal striatal signal processing and to drug-induced abnormal involuntary movements. Determining how such compartmentalization is altered will require a better understanding of the D2R-RGS9-2 interaction suggested by our previous studies. Thus we will continue with our studies that will test if the targeting RGS9-2 toD2R involves a direct or indirect interaction and map the interacting surfaces. We will also attempt to reconstitute coupling between D2R and ion channels, such as NMDA-receptors that generate and shape striatal signals. We will test if co-expressed RGS9-2 can alter D2R-channel coupling. From a parallel clinical study we have identifed non-synonymous mutations and intronic deletions in the RGS9 gene that are enriched in patients with schizophrenia and Parkinson's disease. Thus we will test the hypothesis that these RGS9 gene variations produce alterations in RGS9-2 cellular functions.